Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination

ABSTRACT

Aerosol solution compositions intended for use with a pressurized metered dose inhaler, comprising glycopyrronium bromide and formoterol, or a salt thereof, optionally in combination with one or more additional active ingredients, and stabilized by a selected amount of a mineral acid, exhibit improved stability when contained in an aerosol can provided with a metering valve having at least a butyl rubber gasket.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.13199783.5, filed on Dec. 30, 2013, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to stable aerosol solution compositions,comprising glycopyrronium bromide and formoterol, or a salt thereof or asolvate of said salt, optionally in combination with an inhalationcorticosteroid (ICS), stabilized by a mineral acid, which are containedin an aerosol can. The present invention also relates to methods oftreating and/or preventing certain diseases and conditions byadministering such a composition contained in such an aerosol can.

2. Discussion of the Background

Glycopyrronium bromide (also known as glycopyrrolate) is a muscarinic M3anticholinergic agent used to reduce salivation associated withadministration of certain anaesthetics, and as adjunctive therapy forpeptic ulcers. It has also been reported to be effective in thetreatment of asthmatic symptoms (Hansel et al., Chest 2005;128:1974-1979, which is incorporated herein by reference in itsentirety).

WO 2005/107873, which is incorporated herein by reference in itsentirety, relates to the use of glycopyrrolate for the treatment ofchildhood asthma.

WO 01/76575, which is incorporated herein by reference in its entirety,discloses a controlled release formulation for pulmonary delivery ofglycopyrrolate. The formulation is intended for use in the treatment ofrespiratory diseases, in particular of chronic obstructive pulmonarydisease (COPD). The patent application focuses, essentially, on drypowder formulations suitable for delivery by means of a dry powderinhaler (DPI).

WO 2005/074918, which is incorporated herein by reference in itsentirety, discloses combinations of glycopyrrolate with glucocorticoiddrugs and their use for treating diseases of the respiratory tract.

WO 2005/110402, which is incorporated herein by reference in itsentirety, discloses combinations of glycopyrrolate with a beta-2 agonistof the class of indane or of benzothiazole-2-one derivatives for thetreatment of inflammatory or of obstructive airway diseases.

WO 2006/105401, which is incorporated herein by reference in itsentirety, discloses combinations of an anticholinergic, a corticosteroidand a long-acting beta-2 agonist for the prevention and treatment ofrespiratory, inflammatory or obstructive airway diseases; glycopyrrolateis among the optional anticholinergic agents.

According to WO 2007/057223 and WO 2007/057222, both of which areincorporated herein by reference in their entireties, combinations ofglycopyrronium bromide with an anti-inflammatory steroid, particularlymometasone furoate, are reported to provide a therapeutic benefit in thetreatment of inflammatory and obstructive airways diseases.

WO 2007/057221 and WO 2007/057219, both of which are incorporated hereinby reference in their entireties, respectively, relate to combinationsof a glycopyrronium salt with an indanyl derivative beta-2 agonist (oranalogue) or with an anti-inflammatory steroid, particularly mometasonefuroate.

WO 00/07567, which is incorporated herein by reference in its entirety,discloses, in Example 4, a suspension aerosol formulation wherein to amixture of micronized actives, namely formoterol fumarate,glycopyrronium bromide and disodium cromoglycate, a propellant mixtureof HFA and dinitrogen monoxide, together with 2% by weight of ethanol,are added.

The “Martindale. The complete drug reference,” January 2002, monographon glycopyrronium bromide (page 467), which is incorporated herein byreference in its entirety, shows that in investigations on compatibilityof this substance with aqueous infusion solutions for injections andadditives, the stability of glycopyrronium bromide is questionable abovea pH 6, owing to ester hydrolysis.

US 2002/025299, which is incorporated herein by reference in itsentirety, discloses pressurized aerosol solution formulations ofdifferent active ingredients among which is formoterol or itscombinations with beclometasone dipropionate, further acidified by HCland stored in given cans such as stainless steel or anodized aluminium,or even lined with an inert organic coating.

WO 2005/074900, which is incorporated herein by reference in itsentirety, discloses an inhalable combination of an anticholinergic agentwith a beta-2 mimetic agent for the treatment of inflammatory orobstructive respiratory diseases and, in the examples shows formulationsof the R,R-enantiomer of glycopyrronium bromide in combination withformoterol, either as DPI formulation or pMDI suspension.

US 2006/0257324, which is incorporated herein by reference in itsentirety, discloses the delivery of a combination of two or moredissolved drugs in a HFA propellant-cosolvent system, substantiallyhaving the same particle size distribution and thus allowing for theirco-deposition in the same lung region tract. These formulations comprisea beta-2 agonist (formoterol or carmoterol being exemplified) and acorticosteroid (beclometasone dipropionate being exemplified), or ananticholinegic agent such as ipratropium, oxitropium, tiotropium orglycopyrronium bromide, these latter being only generically cited in thedescription.

Formoterol is a beta-2 adrenergic agonist drug capable of relaxingsmooth muscle in the bronchi and opening the airways to reduce wheezingconditions. It is commonly used in the management of asthma and otherrespiratory conditions.

Recently, an effective combination therapy comprising formoterolfumarate and beclometasone dipropionate (BDP) has become available underthe trade-name Foster®. Said product is designed to be delivered to thelungs through a variety of aerosol means also including pressurizedmetered dose inhalers (pMDI).

In this respect, it is known that aerosol solutions of formoterolfumarate are relatively unstable and have a short shelf-life when storedunder suboptimal conditions. To obviate to this drawback, the Foster®composition has been properly developed by incorporating a suitableamount of inorganic acid in order to stabilize the formoterol componentat a selected apparent pH range, for instance as described in EP 1 157689, which is incorporated herein by reference in its entirety.

In WO 2011/076843, which is incorporated herein by reference in itsentirety, it is disclosed that pMDI aerosol solution formulationscomprising glycopyrronium bromide in combination with formoterol orsalts thereof, optionally including an inhalation corticosteroid such asBDP, wherein a suitable amount of a mineral acid was added, inparticular 1M HCl in the range of 0.1-0.3 μg/μl, so that both formoteroland glycopyrronium bromide components were properly stabilized. Inaddition, the above compositions enabled maintaining the amount of adegradation product, therein referred to as DP3, to low levels.

However, when using relatively high amounts of acid as a stabilizingadjuvant to both formoterol and glycopyrronium components, the amount ofDP3 being detected upon storage for 3 months at 25° C. and 60% ofrelative humidity (RH), were indeed remarkable.

Therefore, as disclosed in WO 2011/076843, which is incorporated hereinby reference in its entirety, a further step comprising removal ofoxygen from the aerosol canister headspace, for instance byincorporating an oxygen purging step through vacuum crimping in theprocess of filling the aerosol canister, may be thus required so as tolower DP3 content.

During the formulation development of such combinations, the degradationproduct DP3 was then identified as beingN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide(see analytical details in the experimental section).

As the formation of this degradation product, when it is quantifiedsignificantly above the identification/qualification threshold (≧1.0%w/w with respect to the theoretical formoterol fumarate content of 6μg/actuation [as defined in ICH Guideline Q3B(R2)]) may represent apotential issue for these pMDI combination formulations, means forlowering the DP3 content below an acceptable threshold, other than thoseknown, involving oxygen removal and requiring a dedicated purging stepin the filling of the aerosol canister during manufacturing, could beparticularly advantageous.

As such, it would be thus desirable to provide a clinically usefulaerosol combination product that combines the therapeutic benefits offormoterol or salts thereof or a solvate of said salt and glycopyrroniumbromide, optionally in conjunction with additional active ingredientssuch as inhalation corticosteroid, in particular beclometasonedipropionate or budesonide, so that each individual pharmaceuticallyactive component is properly delivered to the lungs in effective andconsistent doses over an extended product lifetime, and ideally withoutthe need for particular storage conditions of temperature or humidity,that could be otherwise required to maintain low levels of degradationproducts such as DP3.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelstable aerosol solution compositions, comprising glycopyrronium bromideand formoterol, or a salt thereof or a solvate of said salt, optionallyin combination with an inhalation corticosteroid (ICS), stabilized by amineral acid, which are contained in an aerosol can.

It is another object of the present invention to provide novel methodsof treating and/or preventing certain diseases and conditions byadministering such a composition contained in such an aerosol can.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat once suitably stored in an aerosol can provided with a meteringvalve having at least a butyl rubber gasket which may be selected from achlorobutyl or bromobutyl rubber gasket and in particular with ametering valve wherein all the gaskets are made with a butyl rubber, theamounts of degradation products during their shelf-life, particularly ofDP3 may be minimized even below the detection threshold as determinedafter storage under severe conditions of temperature and humidity.

Thus, the present invention provides aerosol solution compositionsintended for use with a pressurized metered dose inhaler (pMDI),comprising glycopyrronium bromide and formoterol, or a salt thereof or asolvate of said salt, optionally in combination with an inhalationcorticosteroid (ICS), stabilized by a selected amount of a mineral acid,the said composition being contained in an aerosol can provided with ametering valve having at least a butyl rubber gasket.

More in particular, the present invention provides for the above pMDIcompositions that, when stored in an aerosol can provided with theafore-mentioned metering valve for a prolonged period of time undersevere conditions of temperature and relative humidity (RH), show anamount of degradation products, particularly ofN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamidewell below the limit of quantification (i.e. lower than 0.10% w/w withrespect to the theoretical formoterol fumarate content of 6μg/actuation).

The present invention further provides the use of such stable aerosolsolution compositions in the prevention and therapy of airway diseases,particularly of obstructive respiratory disorders such as asthma andCOPD.

More specifically, the present invention provides a pharmaceuticalaerosol solution composition intended for use in a pressurized metereddose inhaler comprising:

(a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μgper actuation;

(b) formoterol, or a salt thereof or a solvate of said salt, at a dosagein the range of from 1 to 25 μg per actuation;

(c) a HFA propellant;

(d) a co-solvent;

(e) a stabilizing amount of a mineral acid;

wherein said composition being contained in an aerosol can provided witha metering valve having at least a butyl rubber gasket.

According to the present invention, the amount of the degradationproduct N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide, hereinafter shortly referred toas DP3, is lower than 0.10% w/w with respect to the theoreticalformoterol fumarate content of 6 μg/actuation, which is the limit ofquantification, when stored in accelerated conditions at 25° C. and 60%relative humidity (RH) for at least 6 months.

Optionally, the composition further comprises an inhalationcorticosteroid selected from the group consisting of beclometasonedipropionate, mometasone furoate, budesonide, flunisolide, fluticasonepropionate, fluticasone furoate, ciclesonide, triamcinolone,triamcinolone acetonide, methylprednisolone, and prednisone.

In another aspect, the present invention provides an aerosol canprovided with a metering valve having at least a butyl rubber gasket foruse with a pharmaceutical aerosol solution composition intended for usein a pressurized metered dose inhaler, comprising:

(a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μgper actuation;

(b) formoterol, or a salt thereof or a solvate of said salt at a dosagein the range of from 1 to 25 μg per actuation;

(c) a HFA propellant;

(d) a co-solvent;

(e) a stabilizing amount of a mineral acid; and, optionally,

(f) an inhalation corticosteroid.

In yet another aspect, the present invention provides a method to lowerthe amount of degradation productN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide(DP3) during the shelf-life of a pharmaceutical aerosol solutioncomposition intended for use in a pressurized metered dose inhalercomprising:

(a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μgper actuation;

(b) formoterol, or a salt thereof or a solvate of said salt at a dosagein the range of from 1 to 25 μg per actuation;

(c) a HFA propellant;

(d) a co-solvent;

(e) a stabilizing amount of a mineral acid; and, optionally,

(f) an inhalation corticosteroid,

said method comprising containing the above composition in an aerosolcan provided with a metering valve having at least a butyl rubbergasket.

In yet another aspect, the present invention provides the use of anaerosol can provided with a metering valve having at least a butylrubber gasket, as a container for a pharmaceutical aerosol solutioncomposition intended for use in a pressurized metered dose inhalercomprising:

(a) glycopyrronium bromide at a dosage in the range of from 5 to 26 μgper actuation;

(b) formoterol, or a salt thereof or a solvate of said salt at a dosagein the range of from 1 to 25 μg per actuation;

(c) a HFA propellant;

(d) a co-solvent;

(e) a stabilizing amount of a mineral acid; and, optionally,

(f) an inhalation corticosteroid.

In a further aspect, the present invention provides the use of anaerosol composition as above described for the prevention and/ortreatment of an obstructive respiratory disorder, including asthma andCOPD.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It has been found unexpectedly that in a pharmaceutical aerosol solutioncomposition intended for use in a pressurized metered dose inhalercomprising:

(a) glycopyrronium bromide at a dosage in the range from 5 to 26 μg peractuation;

(b) formoterol, or a salt thereof or a solvate of said salt at a dosagein the range from 1 to 25 μg per actuation;

(c) a HFA propellant;

(d) a co-solvent;

(e) a stabilizing amount of a mineral acid; and, optionally,

(f) an inhalation corticosteroid,

by the use of a metal aerosol can provided with a specific meteringvalve having at least a butyl rubber gasket, it is possible to maintainthe level of the degradation productN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide, formed by interaction offormoterol and glycopyrronium bromide, when the composition is stored inaccelerated conditions at 25° C. and 60% relative humidity (RH) for atleast 6 months, lower than 0.10% w/w, which is the limit ofquantification (with respect to the theoretical formoterol fumaratecontent of 6 μg/actuation), independently from the can type used.

The pressurized aerosol solution composition of the present combinationmanufactured with a can provided with this specific metering valve,after storage for 6 months at 25° C. and 60% RH, in addition tomaintaining the degradation product DP3 level lower than the limit ofqualification of 0.10% w/w (with respect to the theoretical formoterolfumarate content of 6 μg/actuation) showed an overall formoteroldegradation products level within acceptable limits lower than 10% w/w(with respect to the theoretical formoterol fumarate content of 6μg/actuation), preferably lower than 3% w/w and most preferably lowerthan 2% w/w and the maintained the residual level of formoterolfumarate, the most instable component of the composition, higher than90% w/w, preferably higher than 92% and most preferably higher than 95%w/w with respect to its initial content.

Glycopyrronium bromide and the optional inhalation corticosteroid levelswere maintained almost the same as the respective initial levels.

Other kinds of valves available in the market were not able to keepstrictly under control the formation of the specific degradation productand the relevant chemical stability profile of the components of saidcombination.

Glycopyrronium bromide, chemically defined as3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide, has two chiral centres corresponding to four potentialdifferent stereoisomers with configurations (3R,2′R), (3S,2′R),(3R,2′S), and (3S,2′S). Glycopyrronium bromide in the form of any ofthese pure enantiomers or diastereomers or any combination thereof maybe used in practising the present invention. In one embodiment of theinvention the (3S,2′R),(3R,2′S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide racemic mixture, defined as the threo mixture, also known asglycopyrrolate, is preferred. Glycopyrronium bromide is present in theformulation in an amount of 0.005 to 0.14% (w/w), preferably 0.008 to0.090% (w/w), more preferably 0.01 to 0.045% (w/w), wherein % (w/w)means the amount by weight of the component, expressed as percent withrespect to the total weight of the composition.

Glycopyrrolate is commercially available, and can be synthesizedaccording to the process described in U.S. Pat. No. 2,956,062 or inFranko B V and Lunsford C D, J Med Pharm Chem 2(5), 523-540, 1960, bothof which are incorporated herein by reference in their entireties.

Formoterol, normally used in therapy as the racemic mixture (R,R), (S,S)is chemically defined as (±),(R*,R*)-N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide,and can be in the form of the free base, or as a salt or a solvatethereof. Preferably the formoterol is provided in the form of itsfumarate salt and more preferably the solvate form of the formoterolsalt is formoterol fumarate dihydrate. Formoterol fumarate can, forinstance, be employed in the formulation in an amount of 0.002 to 0.08%w/w, preferably 0.005 to 0.02% w/w.

It is preferred that the pharmaceutically active components of thecomposition are completely and homogeneously dissolved in the mixture ofpropellant and co-solvent, i.e. the composition is preferably a solutionformulation.

Being that the present invention relates to a solution formulationwherein the active ingredients are completely dissolved in theformulation, when the description generically cites formoterol fumarate,both the forms of formoterol fumarate and formoterol fumarate dihydrate,which is its solvate form available in the market, are intended.

The co-solvent incorporated into the formulations of the presentinvention has a higher polarity than that of the propellant and mayinclude one or more substances such as a pharmaceutically acceptablealcohol or polyol in an amount able to solubilize the pharmaceuticallyactive components of the composition (formoterol fumarate,glycopyrronium bromide and optionally an inhalation corticosteroid) inthe propellant.

Advantageously the alcohol co-solvent is selected from the group oflower branched or linear alkyl (C₁-C₄) alcohols such as ethanol andisopropyl alcohol. Preferably the co-solvent is ethanol.

Advantageously the polyol cosolvent is selected from glycerol, propyleneglycol or polyethylene glycol.

The concentration of the co-solvent will vary depending on the finalconcentration of the active ingredient in the formulation and on thetype of propellant. For example ethanol may be used in a concentrationof 5 to 30% (w/w), preferably 8 to 25% (w/w), more preferably 10 to 15%(w/w). In one of the preferred embodiments, the concentration of ethanolis about 12% (w/w).

The propellant component of the composition may be anypressure-liquefied propellant and is preferably a hydrofluoroalkane(HFA) or a mixture of different HFAs, more preferably selected from thegroup consisting of HFA 134a (1,1,1,2-tetrafluoroethane), HFA 227(1,1,1,2,3,3,3-heptafluoropropane), and mixtures thereof. The preferredHFA is HFA 134a. HFAs may be present in the composition in an amount inthe range from 70 to 95% (w/w), preferably from 85 to 90% (w/w).

The ratio of propellant to co-solvent in the composition is in the rangefrom 70:30 to 95:5 (w/w).

The stabilizing amount of a mineral acid, sufficient to stabilizeglycopyrronium bromide and formoterol, is an amount of acid equivalentto 1M hydrochloric acid (HCl) in the range of 0.1 to 0.3 μg/μl offormulation, preferably 0.15 to 0.28 μg/μl, more preferably 0.18 to 0.26μg/μl, and in particular 0.22 μg/μl of formulation.

HCl of different molarity or alternative inorganic acids (mineral acids)may be substituted for 1M HCl in the composition of the invention. Forinstance, using an acid at a concentration different from 1M HCl, itsamount must be proportioned with respect to the concentration, accordingto calculation steps known to the skilled person.

Alternative acids may be any pharmaceutically acceptable monoprotic orpolyprotic acid, such as (but not limited to): hydrogen halides(hydrochloric acid, hydrobromic acid, hydroiodic acid etc.) phosphoricacid, nitric acid, sulfuric acid, and halogen oxoacids.

Optionally, the aerosol solution composition may comprise otherpharmaceutical excipients or additives known in the art. In particular,the compositions of the invention may comprise one or more lowvolatility components. Low volatility components are useful in order toincrease the mass median aerodynamic diameter (MMAD) of the aerosolparticles upon actuation of the inhaler and/or to improve the solubilityof the active ingredient in the propellant/co-solvent mixture.

The low volatility component, when present, has a vapour pressure at 25°C. lower than 0.1 kPa, preferably lower than 0.05 kPa. Examples oflow-volatility components are esters such as isopropyl myristate,ascorbyl myristate, tocopherol esters; glycols such as propylene glycol,polyethylene glycol, glycerol; and surface active agents such assaturated organic carboxylic acids (e.g. lauric, myristic, stearic acid)or unsaturated carboxylic acids (e.g. oleic or ascorbic acid).

The amount of low volatility component may vary from 0.1 to 10% w/w,preferably from 0.5 to 5% (w/w), more preferably between 1 and 2% (w/w).

In another embodiment, an amount of water comprised between 0.005 and0.3% (w/w) may optionally be added to the compositions in order tofavourably affect the solubility of the active ingredient withoutincreasing the MMAD of the aerosol droplets upon actuation.

Advantageously, the compositions of the present invention are free ofexcipients (such as surfactants) other than co-solvent, propellant and astabilizing amount of an acid.

The pharmaceutical compositions of the present invention may furthercomprise one or more additional pharmaceutically active agents forseparate, sequential or simultaneous use. The one or more additionalpharmaceutically active agent of the composition includes any activeingredient known in the art for prophylaxis or treatment of respiratorydiseases and their symptoms. Examples of one or more additionalpharmaceutically active agent are selected from the following classes:

beta-2 agonist, selected from the group of salbutamol, fenoterol,carmoterol (TA-2005; CHF 4226), indacaterol, milveterol, vilanterol (GSK642444), olodaterol, abediterol, terbultaline, salmeterol, bitolterol,metaproterenol and a salt thereof, optionally in form of a singlestereoisomer or of a mixture thereof;

inhalation corticosteroid, selected from the group of beclometasonedipropionate, budesonide or its 22R-epimer, ciclesonide, flunisolide,fluticasone propionate, fluticasone furoate, mometasone furoate,butixocort, triamcinolone acetonide, triamcinolone, methylprednisolone,prednisone, loteprednol and rofleponide;

anti-muscarinic drug selected from methscopolamine, ipratropium,oxitropium, trospium, tiotropium, aclidinium and umeclidinium as bromidesalt or a salt with any other pharmaceutically acceptable counter ion;and

phosphodiesterase-4 (PDE-4) inhibitor selected from CHF 6001,cilomilast, roflumilast, tetomilast, oglemilast and a salt thereof.

In a preferred embodiment, the composition of the present inventioncomprises an inhalation corticosteroid selected from beclometasonedipropionate (BDP), budesonide, fluticasone furoate, fluticasonepropionate and mometasone furoate in addition to formoterol fumarate andglycopyrronium bromide components. In that embodiment the more preferredinhalation corticosteroid is selected from BDP and budesonide. BDP orbudesonide are present in an amount of 0.02 to 0.8% w/w, more preferably0.042 to 0.43% w/w. The most preferred inhalation corticosteroid is BDP.

The compositions of the present invention can be inhaled from anysuitable known pressurized MDI device. Desired doses of the individualpharmaceutically active components of the formulation are dependent onthe identity of the component and the type and severity of the diseasecondition, but are preferably such that a therapeutic amount of theactive ingredient is delivered in one or two actuations. Generallyspeaking, doses of active ingredient are in the range of about 0.5 to1000 μg per actuation, e.g. about 1 to 300 μg/actuation, and sometimesabout 5 to 150 μg/actuation. The skilled person in the field is familiarwith how to determine the appropriate dosage for each individualpharmaceutically active ingredient.

With reference to formoterol fumarate in its dihydrate form, thepreferred dosage is in the range of 1 to 24 μg per actuation, morepreferably in the range of 6 to 12 μg per actuation. In a specificembodiment, the dose of formoterol fumarate dihydrate is of 6 or 12 μgper actuation.

With reference to glycopyrronium bromide, the preferred dosage is in therange of 5 to 26 μg per actuation more preferably in the range of 6 to25 μg per actuation. In a specific embodiment, the dose ofglycopyrronium bromide is of 6, 12.5, or 25 μg per actuation.

With reference to the optional component, when it is selected from aninhalation corticosteroid, the preferred dosage is in the range of 20 to1000 μg per actuation, preferably in the range of 50 to 250 μg peractuation. In specific embodiments, the dose of beclometasonedipropionate and of budesonide is 50, 100, or 200 μg per actuation.

The pharmaceutical composition of the present invention is filled intopMDI devices known in the art. Said devices comprise a can fitted with ametering valve. Actuation of the metering valve allows a small portionof the spray product to be released.

Part or all of the cans known in the art may be made of a metal, forexample aluminium, aluminium alloy, stainless steel or anodizedaluminium. Alternatively the canister may be a plastic can or aplastic-coated glass bottle.

Metal canisters for pMDI may have part or all of their internal surfaceslined or passivated with an inert organic or inorganic coating appliedby conventional coating or by plasma coating. Examples of such coatingsare epoxy-phenol resins, perfluorinated polymers such asperfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes suchas poly-tetrafluoroethylene (Teflon), fluorinated-ethylene-propylene(FEP), polyether sulfone (PES) or fluorinated-ethylene-propylenepolyether sulfone (FEP-PES) mixtures or combination thereof. Othersuitable coatings could be polyamide, polyimide, polyamideimide,polyphenylene sulfide or their combinations.

Suitable cans are available from manufacturers such as, for instance,3M, Presspart and Pressteck.

The can is closed with a metering valve for delivering a therapeuticallyeffective dose of the active ingredients. Generally, the metering valveassembly comprises a ferrule having an aperture formed therein, a bodymolding attached to the ferrule which houses the metering chamber, astem consisting of a core and a core extension, an inner- and anouter-seal around the metering chamber, a spring around the core, and agasket to prevent leakage of propellant through the valve.

The gasket seal and the seals around the metering valve may comprise thesame or different elastomeric material selected from EPDM (ethylenepropylene diene monomer), neoprene and butyl rubber. Among the butylrubber, chlorobutyl rubber and bromobutyl rubber are preferred andchlorobutyl rubber is particularly preferred. The most preferredmetering valve has all the seals made with the same elastomeric materialwhich is selected from a butyl rubber and in particular from achlorobutyl rubber or a bromobutyl rubber.

The metering chamber, core and core extension are manufactured usingsuitable materials such as stainless steel, polyesters (e.g.polybutyleneterephthalate (PBT)), or acetals. The spring is manufacturedin stainless steel eventually including titanium. The ferrule may bemade of a metal, for example aluminium, aluminium alloy, stainless steelor anodized aluminium. Suitable valves are available from manufacturerssuch as, for instance, Valois-Aptar, Bespak plc, V.A.R.I., 3M-NeotechnicLtd, Rexam, Coster.

The pMDI is actuated by a metering valve capable of delivering a volumein the range of 25 to 150 μl, preferably in the range of 50 to 100 μl,and more preferably 50 μl or 63 μl per actuation.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs of a patient. Suitable channelling devicescomprise, for example a valve actuator and a cylindrical or cone-likepassage through which medicament may be delivered from the filledcanister via the metering valve to the mouth of a patient, e.g. amouthpiece actuator.

In a typical arrangement the valve stem is seated in a valve stemreceptacle into the nozzle block which has an orifice leading to anexpansion chamber. The expansion chamber has an exit orifice whichextends into the mouthpiece. Actuator exit orifices having a diameter inthe range of 0.15 to 0.45 mm and a length of 0.30 to 1.7 mm aregenerally suitable. Preferably, an orifice having a diameter of 0.2 to0.45 mm is used, e.g. 0.22, 0.25, 0.30, 0.33, or 0.42 mm.

In certain embodiments of the present invention, it may be useful toutilize actuator orifices having a diameter of 0.10 to 0.22 mm, inparticular 0.12 to 0.18 mm, such as those described in WO 03/053501,which is incorporated herein by reference in its entirety. The use ofsaid fine orifices may also increase the duration of the cloudgeneration and hence, may facilitate the coordination of the cloudgeneration with the slow inspiration of the patient.

Suitable actuators for the delivery of the composition of the presentinvention are the conventional ones, wherein the longitudinal axis ofthe can (aligned with the longitudinal axis of the valve stemreceptacle) is inclined of an angle greater or equal to 90° with respectto the longitudinal axis of the mouthpiece which is in general alignedwith actuator orifice, but also an actuator according to WO 2012/032008,which is incorporated herein by reference in its entirety, wherein thelongitudinal axis of the actuator exit orifice is aligned with thelongitudinal axis of the valve stem receptacle, may be used.

Other suitable actuators for the delivery of the composition of thepresent invention are those disclosed in WO 2014/033057, which isincorporated herein by reference in its entirety, wherein the nozzleblock orifice is characterised by the presence of a tubular elementextending in the mouthpiece portion from the orifice aperture in alongitudinal axis aligned with a longitudinal axis of the mouthpieceportion. In particular said tubular element is positioned to enclose theorifice aperture within a recess.

In case the ingress of water into the formulation is to be avoided, itmay be desired to overwrap the MDI product in a flexible package capableof resisting water ingress. It may also be desirable to incorporate amaterial within the packaging which is able to adsorb any propellant andco-solvent which may leak from the canister (e.g. a molecular sieve).

Optionally the MDI device filled with the composition of the presentinvention may be utilized together with suitable auxiliary devicesfavoring the correct use of the inhaler. Said auxiliary devices arecommercially available and, depending on their shape and size, are knownas “spacers,” “reservoirs,” or “expansion chambers.” Volumatic™ is, forinstance, one of the most widely known and used reservoirs, whileAerochamber™ is one of the most widely used and known spacers. Asuitable expansion chamber is reported for example in WO 01/49350, whichis incorporated herein by reference in its entirety.

The composition of the present invention may also be used with commonpressurized breath-activated inhalers, such as those known with theregistered names of Easi-Breathe™ and Autohaler™.

In addition, the composition of the present invention may beadministered through an actuator provided with a mechanical orelectronic dose counter or dose indicator known in the art which may betop-mounted externally to the actuator or integrated internally to theactuator. Such a dose counter or dose indicator may show, respectively,the number or the range of the doses administered and/or the number orthe range of the doses still remaining into the can.

The efficacy of an MDI device is a function of the dose deposited at theappropriate site in the lungs. Deposition is affected by the aerodynamicparticle size distribution of the formulation which may be characterisedin vitro through several parameters.

The aerodynamic particle size distribution of the composition of thepresent invention may be characterized using a cascade impactoraccording to the procedure described in the European Pharmacopoeia7^(th) edition, 2013 (7.8), part 2.9.18, which is incorporated herein byreference in its entirety. An Apparatus E, operating at a flow raterange of 30 l/min to 100 l/min is used. Deposition of the drug on eachcascade impactor cup is determined by high performance liquidchromatography (HPLC).

The following parameters of the particles emitted by a pressurized MDImay be determined:

-   -   i) mass median aerodynamic diameter (MMAD) is the diameter        around which the mass aerodynamic diameters of the emitted        particles are distributed equally;    -   ii) delivered dose is calculated from the cumulative deposition        in the cascade impactor, divided by the number of actuations per        experiment;    -   iii) respirable dose (fine particle dose=FPD) corresponds to the        mass of particles of diameter≦5 microns, divided by the number        of actuations per experiment;    -   iv) respirable fraction (fine particle fraction=FPF) is the        percent ratio between the respirable dose and the delivered        dose;    -   v) “superfine” dose is obtained from the deposition from cup 6        (C6) to filter, corresponding to particles of diameter 1.4        microns, divided by the number of actuations per experiment.

The solutions of the present invention are capable of providing, uponactuation of the pMDI device in which they are contained, a total FPFhigher than 25%, preferably higher than 30%, more preferably higher than35%.

Moreover the compositions of the present invention are capable ofproviding, upon actuation, a fraction higher than or equal to 15% ofemitted particles of diameter equal to or less than 1.4 microns asdefined by the content cups from C6 to filter (C6-F) of the cascadeimpactor, relative to the total fine particle dose collected in the cupsfrom C3 to filter (C3-F) of the impactor. Preferably the fraction ofemitted particles of diameter equal to or less than 1.4 microns ishigher than or equal to 20%, more preferably higher than 25%.

According to a further aspect of the present invention, there isprovided a method of filling an aerosol inhaler with a composition ofthe present invention. Conventional bulk manufacturing methods andmachinery well-known in the art of pharmaceutical aerosol manufacturemay be employed for the preparation of large-scale batches for thecommercial production of filled canisters.

A first method comprises:

-   -   a) preparing a solution of glycopyrronium bromide, formoterol        fumarate and optionally of the inhalation corticosteroid,        preferably selected from beclometasone dipropionate and        budesonide in a co-solvent (e.g. ethanol), mineral acid,        propellant comprising a HFA, and an optional low volatility        component at a temperature from −50 to −60° C. at which the        composition does not vaporize;    -   b) cold-filling the can with the prepared solution; and    -   c) placing the valve onto the empty can and crimping.

An alternative method comprises:

-   -   a) preparing a solution of glycopyrronium bromide, formoterol        fumarate and optionally of the inhalation corticosteroid,        preferably selected from beclometasone dipropionate and        budesonide in a co-solvent (e.g. ethanol), mineral acid, and an        optional low volatility component;    -   b) filling the open can with the bulk solution;    -   c) placing the valve onto the can and crimping; and    -   d) pressure-filling the can with the HFA propellant through the        valve

A further alternative method comprises:

-   -   a) preparing a solution of glycopyrronium bromide, formoterol        fumarate and optionally of the inhalation corticosteroid,        preferably selected from beclometasone dipropionate and        budesonide, in a co-solvent (e.g. ethanol), mineral acid, a        propellant comprising a HFA and an optional low volatility        component using a pressurized vessel:    -   b) placing the valve onto the empty can and crimping; and    -   c) pressure-filling the can with the final solution through the        valve.

In one embodiment of the present invention, oxygen is substantiallyremoved from the headspace of the aerosol canister using conventionaltechniques in order to further stabilize the formoterol component,especially at higher acid concentrations. This can be achieved indifferent ways depending on the method of filling the container. Purgingcan be achieved by vacuum crimping or by using propellant, for instance.In a preferred embodiment, the second filling method described above ismodified to incorporate an oxygen purging step into step (c) by vacuumcrimping.

The packaged composition of the present invention is stable for extendedperiods of time when stored under normal conditions of temperature andhumidity. In a preferred embodiment, the packaged composition are stablefor over 6 months at 25° C. and 60% RH, more preferably for at least 9months. Stability is assessed by measuring content of residual activeingredient and content of impurities/degradation products. A “stable”composition as defined herein means that the content of residual activeingredient is of at least about 90% w/w (which is the content percent byweight with respect to its initial content at time 0), preferably of atleast about 95% w/w, and that the total content of degradation productis of not more than about 10% by weight with respect to initial contentof the active ingredient at time 0, preferably of not more than about 5%by weight, at a given time point, as measured by HPLC/UV-VIS.

The optimized stable compositions meet the specifications required bythe ICH Guideline Q1A(R2) relevant for drug product stability testingfor the purposes of drug registration.

The combination product compositions of the present invention may beused for prophylactic purposes or therapeutic purposes or forsymptomatic relief of a wide range of conditions, and, in one aspect,the present invention therefore relates to use of any of thesepharmaceutical compositions as a medicament. In particular, thecombination products of the present invention are useful for theprevention or treatment of many respiratory disorders, such as asthma ofall types and chronic obstructive pulmonary disease (COPD).

Thus, in another aspect the present invention relates to a method ofpreventing and/or treating a respiratory disease, such as asthma andCOPD, comprising administering to a patient in need of such treatment atherapeutically effective amount of a pharmaceutical compositionaccording to the present invention.

The present invention also provides the use of the pharmaceuticalcompositions of the present invention for the therapeutic or palliativetreatment or prevention of respiratory diseases and their symptoms.

Respiratory disorders for which use of the pharmaceutical compositionsof the present invention may also be beneficial are those characterizedby obstruction of the peripheral airways as a result of inflammation andpresence of mucus, such as chronic obstructive bronchiolitis, chronicbronchitis, emphysema, acute lung injury (ALI), cystic fibrosis,rhinitis, and adult or acute respiratory distress syndrome (ARDS).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Stability of a Triple Combination Aerosol SolutionComposition Stored at 25° C. and 60% Relative Humidity (RH)

A study was performed to investigate the stability of a triplecombination of formoterol fumarate (FF), glycopyrronium bromide (GLY),and beclometasone dipropionate (BDP) in an aerosol solution formulationwhose composition is shown in Table 1 and which was stored for 6 monthsat 25° C. and 60% relative humidity (RH), in different kinds of can,crimped with different kinds of valve.

TABLE 1 Composition of the aerosol solution composition of the triplecombination of formoterol fumarate (FF) dihydrate, glycopyrroniumbromide (GLY) and beclometasone dipropionate (BDP). Content % w/w meansthe percent content by weight of each component with respect to thetotal weight of the composition. Mass in μg per Mass in Content %Component actuation (63 μL) μg/μL (w/w) BDP 100 1.59 0.135 FF dihydrate6 0.095 0.0081 GLY 12.5 0.20 0.0169 Ethanol (anhydrous) 8856 140.5712.000 1M HCl 14 0.22 0.0019 HFA 134a 64811.5 1028.75 87.820

Sample batches were stored in inverted orientation, deemed the worstcase condition for the drug product stability, and 3 canisters for eachbatch were analyzed for residual content of active ingredients and totalformoterol degradation products (including DP3: corresponding toN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide) at the 6 months checkpoint.

The DP3 structure was identified by HPLC/MS/MS experiments performed ondegraded samples of a triple combination of formoterol fumarate,glycopyrronium bromide and beclometasone dipropionate in an aerosolsolution formulation.

To attribute the position of the substituting bromine atom, a triplecombination of deuterated formoterol fumarate(N-(3-deutero)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide),glycopyrronium bromide, and beclometasone dipropionate was manufacturedin plain aluminium cans, crimped with valves provided with EPDM(ethylene propylene diene monomer) rubber seals (RB700 from Bespak), andstored at 40° C. and 75% RH for 1 month. The analysis of the degradationproducts pointed out that the deuterium atom of deuterated formoterolfumarate was substituted by the bromine atom giving the degradationproduct DP3. Moreover aN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide standard was synthesized andcharacterized by ¹H-NMR and MS/MS analysis. MS/MS spectrum of theN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide standard showed a fragmentationpattern comparable to the fragmentation pattern of DP3.

The residual content of each active ingredient, DP3, and the totalamount of formoterol degradation products were measured using avalidated HPLC/UV-VIS method. A mass spectra detector was used toconfirm the molecular weights of the detected degradation products foundin each can.

The results, summarized in the following Table 2, after 6 months storageat 25° C./60% relative humidity (RH) as reported, showed that theconfigurations performing the best results in term of higher activeingredient content (in particular of glycopyrronium bromide andformoterol), the lowest levels of total formoterol degradation products(with respect to the theoretical formoterol fumarate content of 6μg/actuation) and, unexpectedly, in degradation product DP3 lower thanthe limit of quantification of 0.10% w/w (with respect to thetheoretical formoterol fumarate content), were those wherein thecomposition was stored in an aerosol can provided with a metering valvehaving a butyl rubber gasket.

Even if as known from WO 2011/076843, cited above, vacuum crimpingimproves the stability of the composition by oxygen removal from theaerosol can; unexpected improvements to the stability were indeedobtained by using an aerosol can provided with a metering valve having abutyl rubber gasket.

The composition of the present invention packaged in an aerosol canprovided with a metering valve having a butyl rubber gasket showed adegradation product DP3 level lower than the limit of quantification of0.10% w/w (with respect to the theoretical formoterol fumarate contentof 6 μg/actuation), total formoterol degradation product levels lowerthan 2% w/w (with respect to the theoretical formoterol fumarate contentof 6 μg/actuation) and the maintenance of formoterol fumarate, the mostinstable component of the composition, residual level higher than 95%w/w after storage in the reported conditions.

TABLE 2 Results of the stability test of Example 1 performed on thecomposition stored 6 months at 25° C. and 60% relative humidity (RH).Total Amount of Formoterol DP3 degradation products Residual ResidualResidual (% w/w with respect to the (% w/w with respect to the FF GLYBDP theoretical formoterol theoretical formoterol Can Valve Crimping (%w/w) (% w/w) (% w/w) fumarate content) fumarate content) Aluminium ButylNormal 94.7 99.9 99.0 <0.10 0.81 plain Rubber 1 Aluminium Butyl Vacuum94.7 99.7 98.9 <0.10 0.88 plain Rubber 1 Aluminium Butyl Normal 96.5100.5 100.0 <0.10 1.7 plain Rubber 2 Aluminium Butyl Normal 95.2 100.599.2 <0.10 2.0 plain Rubber 3 FEP coated Butyl Normal 95.3 102.0 101.1<0.10 1.3 aluminium Rubber 1 FEP coated Butyl Normal 97.2 100.5 100.0<0.10 1.7 aluminium Rubber 2 FEP coated Butyl Normal 94.1 99.5 98.6<0.10 2.2 aluminium Rubber 3 Plasma EPDM 2 Normal 74.5 99.1 99.7 8.9816.0 coated aluminium 2 Plasma EPDM 2 Vacuum 91.8 101.2 100.6 3.40 5.6coated aluminium 2 Plasma EPDM 4 Normal 94.8 98.4 98.3 1.21 2.6 coatedaluminium 2 Plasma EPDM 4 Vacuum 85.2 98.5 98.6 5.00 8.1 coatedaluminium 2 Plasma EPDM 5 Normal 93.5 99.2 99.7 1.9 3.7 coated aluminium2 Anodized EPDM 2 Normal 84.6 96.5 99.4 1.4 4.9 aluminium Anodized EPDM3 Normal 89.0 98.0 99.1 <0.41 4.6 aluminium Anodized Butyl Normal 91.798.3 99.4 0.10 1.9 aluminium Rubber 1 Anodized Butyl Normal 94.4 99.299.2 <0.10 2.4 aluminium Rubber 2 Anodized Butyl Normal 95.2 101.0 99.6<0.10 2.6 aluminium Rubber 3 Plasma coated EPDM 2 Normal 90.6 98.7 99.81.8 3.1 aluminium 3 Plasma coated Butyl Normal 93.4 100.3 100.2 <0.101.3 aluminium 3 Rubber 1 Fluorine EPDM 2 Normal 70.0 96.8 99.7 10.4 14.0passivated aluminium surface Fluorine EPDM 3 Normal 82.4 97.8 99.7 5.28.0 passivated aluminium surface Fluorine EPDM 2 Normal 70.0 96.8 99.710.4 14.0 passivated aluminium surface Fluorine EPDM 3 Normal 82.4 97.899.7 5.2 8.0 passivated aluminium surface Fluorine Butyl Normal 93.9100.2 99.2 <0.10 1.4 passivated Rubber 1 aluminium surface FluorineButyl Normal 96.1 100.0 99.6 <0.10 2.6 passivated Rubber 2 aluminiumsurface Fluorine Butyl Normal 94.7 100.5 99.6 <0.10 2.2 passivatedRubber 3 aluminium surface Aluminium Butyl Normal 97.6 99.5 99.8 <0.101.8 plain Rubber 4 FEP coated Butyl Normal 97.5 99.7 100.0 <0.10 1.7aluminium Rubber 4 Anodized Butyl Normal 97.5 100.2 100.8 <0.10 1.9aluminium Rubber 4 Fluorine Butyl Normal 97.2 99.8 100.0 <0.10 1.9passivated Rubber 4 aluminium surface Plasma coated Butyl Normal 96.699.3 99.2 <0.10 1.8 aluminium 3 Rubber 4 % (w/w), unless specificallydefined, relates to the content by weight of each substance with respectto its initial content in the formulation. Different numbers near eachvalve or can definitions define different kinds of cans or valves fromsame or different suppliers as below reported: VALVES: EPDM 2 and 3represent, respectively, Bespak: BK700 and BK701; EPDM 4 and 5represent, respectively, Aptar 808 and 810; Butyl Rubber 1 to 4represent, respectively, butyl rubber valves from VARI, Rexam, Coster;Butyl Rubber 5 represents bromo-butylic valve Bespak (BK357); Cans: FEPcoated from 3M; Aluminium plain, Anodized aluminium, Plasma coatedaluminium 2 and 3 and fluorine passivated aluminium surface cans werefrom Presspart.

Example 2 Stability of a Further Triple Combination Aerosol SolutionComposition Stored for 6 Months at 25° C. and 60% Relative Humidity (RH)

A study was performed to investigate the stability of a triplecombination of formoterol fumarate (FF), glycopyrronium bromide (GLY),and budesonide in an aerosol solution formulation whose composition isshown in Table 3 and which was stored for 6 months at 25° C. and 60%relative humidity (RH), in different kinds of can, crimped withdifferent kinds of valves.

TABLE 3 Composition of the aerosol solution composition of the triplecombination of formoterol fumarate (FF) dihydrate, glycopyrroniumbromide (GLY), and budesonide. Content % w/w means the percent contentby weight of each component with respect to the total weight of thecomposition. Mass in μg per Mass in Content % Component actuation (63μL) μg/μL (w/w) Budesonide 100 1.59 0.135 FF dihydrate 6 0.095 0.0081GLY 12.5 0.20 0.0169 Ethanol (anhydrous) 8856 140.57 12.000 1M HCl 140.22 0.0019 HFA 134a 64811.5 1028.75 87.820

Sample batches were stored in inverted orientation, deemed the worstcase condition for the drug product stability, and 3 canisters for eachbatch were analyzed for residual content of active ingredients and totalformoterol degradation products (including DP3: corresponding toN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide)at the 6 months checkpoint.

The residual content of each active ingredient, DP3, and the totalamount of formoterol degradation products were measured using avalidated HPLC/UV-VIS method. A mass spectra detector was used toconfirm the molecular weights of the detected degradation products foundin each can.

The results, summarized in the following Table 4, confirmed that, after6 months at 25° C./60% relative humidity (RH), the configurationsperforming the best results in term of higher active ingredient content(in particular of glycopyrronium bromide and formoterol), the lowestlevels of total formoterol degradation products (with respect to thetheoretical formoterol fumarate content of 6 μg/actuation) andunexpectedly in degradation product DP3 lower than the limit ofquantification of 0.10% w/w (with respect to theoretical formoterolfumarate content of 6 μg/actuation), were those wherein the compositionwas stored in a can provided with a butyl rubber valve even in presenceof a different inhalation corticosteroid (budesonide in place of BDP).

TABLE 4 Results of the stability test of Example 2 performed on thecomposition stored for 6 months at 25° C. and 60% relative humidity(RH). Total Amount of Formoterol DP3 degradation products ResidualResidual Residual (% w/w with respect tothe (% w/w wit hrespect to theFF GLY Budesonide theoretical formoterol theoretical formoterol CanValve Crimping (% w/w) (% w/w) (% w/w) fumarate content) fumaratecontent) Fluorine EPDM 2 Normal 91.3 97.3 99.2 1.92 3.9 passivatedaluminium surface Fluorine Butyl Normal 93.7 98.5 99.0 <0.10 0.79passivated Rubber1 aluminium surface Plasma coated EPDM 2 Normal 94.296.7 98.6 0.20 0.85 aluminium 3 Plasma coated Butyl Normal 91.2 98.299.4 <0.10 1.0 aluminium 3 Rubber1 % (w/w), unless specifically defined,relates to the content by weight of each substance with respect to itsinitial content in the formulation. Different numbers near each valve orcan definitions define different kinds of cans or valves from same ordifferent suppliers as below reported: VALVES: EPDM 2 represents BespakBK701; Butyl Rubber 1 represents butyl rubber valve from VARI; Cans:Plasma coated aluminium 3 and fluorine passivated aluminium surface canswere from Presspart.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A pharmaceutical aerosol solution composition, for use in apressurized metered dose inhaler, comprising: (a) glycopyrronium bromideat a dosage in the range of from 5 to 26 μg per actuation; (b)formoterol, or a salt thereof or a solvate of said salt, at a dosage inthe range of from 1 to 25 μg per actuation; (c) a HFA propellant; (d) aco-solvent; (e) a stabilizing amount of a mineral acid; wherein saidcomposition is contained in an aerosol can provided with a meteringvalve having at least a butyl rubber gasket.
 2. A pharmaceutical aerosolsolution composition according to claim 1, wherein the amount of thedegradation productN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamideformed, when said composition is stored in accelerated conditions at 25°C. and 60% relative humidity (RH) for at least 6 months, is lower than0.10% w/w, with respect to the theoretical formoterol fumarate contentof 6 μg/actuation.
 3. A pharmaceutical aerosol solution compositionaccording to claim 1, wherein said mineral acid is present in an amountequivalent to 0.15 to 0.28 μg/μl of 1M hydrochloric acid.
 4. Apharmaceutical aerosol solution composition according to claim 3,wherein said mineral acid is present in an amount of acid equivalent to0.22 μg/μl of 1M hydrochloric acid.
 5. A pharmaceutical aerosol solutioncomposition according to claim 1, wherein said co-solvent is ethanol. 6.A pharmaceutical aerosol solution composition according to claim 1,wherein said formoterol salt is formoterol fumarate.
 7. A pharmaceuticalaerosol solution composition according to claim 1, wherein said solvateform of said formoterol salt is formoterol fumarate dihydrate.
 8. Apharmaceutical aerosol solution composition according to claim 1,further comprising one or more pharmaceutically active ingredientsselected from the group consisting of a beta-2 agonist, an inhalationcorticosteroid, an antimuscarinic agent, and a phosphodiesterase-4inhibitor.
 9. A pharmaceutical aerosol solution composition according toclaim 8, wherein said inhalation corticosteroid is beclometasonedipropionate, budesonide or its 22R-epimer, ciclesonide, flunisolide,fluticasone propionate, fluticasone furoate, mometasone furoate,butixocort, triamcinolone acetonide, triamcinolone, methylprednisolone,prednisone, loteprednol, or rofleponide.
 10. A pharmaceutical aerosolsolution composition according to claim 9, wherein said inhalationcorticosteroid is beclometasone dipropionate which is present in anamount of 50 to 250 μg per actuation.
 11. A pharmaceutical aerosolsolution composition according to claim 9, wherein said inhalationcorticosteroid is budesonide which is present in an amount of 50 to 250μg per actuation.
 12. A pharmaceutical aerosol solution compositionaccording to claim 1, wherein the level of formoterol degradationproducts formed, when said composition is stored in acceleratedconditions at 25° C. and 60% relative humidity (RH) for at least 6months, is lower than 10% w/w with respect to the theoretical formoterolfumarate content of 6 μg/actuation, and wherein the residual level offormoterol fumarate, when said composition is stored in acceleratedconditions at 25° C. and 60% relative humidity (RH) for at least 6months, is higher than 90% w/w with respect to its initial content. 13.A pharmaceutical aerosol solution composition according to claim 12,wherein the overall level of formoterol degradation products formed,when said composition is stored in accelerated conditions at 25° C. and60% relative humidity (RH) for at least 6 months, is lower than 2% w/wwith respect to the theoretical formoterol fumarate content of 6μg/actuation, and wherein the residual level of the formoterol fumarate,when said composition is stored in accelerated conditions at 25° C. and60% relative humidity (RH) for at least 6 months, is higher than 95% w/wwith respect to its initial content.
 14. An aerosol can, comprising ametering valve having at least a butyl rubber gasket and containing apharmaceutical aerosol solution composition comprising: (a)glycopyrronium bromide at a dosage in the range of from 5 to 26 μg peractuation; (b) formoterol, or a salt thereof or a solvate of said salt,at a dosage in the range of from 1 to 25 μg per actuation; (c) a HFApropellant; (d) a co-solvent; (e) a stabilizing amount of a mineralacid; and, (f) optionally, an inhalation corticosteroid.
 15. A method tolower the amount of degradation productN-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide(DP3) formed during the shelf-life of a pharmaceutical aerosol solutioncomposition intended for use in a pressurized metered dose inhalercomprising: (a) glycopyrronium bromide at a dosage in the range of from5 to 26 μg per actuation; (b) formoterol, or a salt thereof or a solvateof said salt, at a dosage in the range of from 1 to 25 μg per actuation;(c) a HFA propellant; (d) a co-solvent; (e) a stabilizing amount of amineral acid; and (f) optionally, an inhalation corticosteroid saidmethod comprising containing the above composition in an aerosol canprovided with a metering valve having at least a butyl rubber gasket.16. A method according to claim 15, wherein the overall level offormoterol degradation products formed, when said composition is storedin accelerated conditions at 25° C. and 60% relative humidity (RH) forat least 6 months, is lower than 10% w/w with respect to the theoreticalformoterol fumarate content of 6 μg/actuation, and wherein the residuallevel of formoterol fumarate, when said composition is stored inaccelerated conditions at 25° C. and 60% relative humidity (RH) for atleast 6 months, is higher than 90% w/w with respect to its initialcontent.
 17. A method according to claim 15, wherein the overall levelof formoterol degradation products formed, when said composition isstored in accelerated conditions at 25° C. and 60% relative humidity(RH) for at least 6 months, is lower than 2% w/w with respect to thetheoretical formoterol fumarate content of 6 μg/actuation, and whereinthe residual level of the formoterol fumarate, when said composition isstored in accelerated conditions at 25° C. and 60% relative humidity(RH) for at least 6 months, is higher than 95% w/w with respect to itsinitial content.
 18. A method for the prevention and/or treatment of anobstructive respiratory disorder selected from the group consisting ofasthma and COPD, comprising administering an effective amount of apharmaceutical aerosol solution composition according to claim 1 to asubject in need thereof.